Neuropeptides, Inflammation, Biofilms, and diabetic Foot Ulcers

Shaoling Yang; Liye Hu; Rui Han; Yiwen Yang

doi:10.1055/a-1493-0458

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2022; 130(07): 439-446
DOI: 10.1055/a-1493-0458

Review

Neuropeptides, Inflammation, Biofilms, and diabetic Foot Ulcers

Authors

Shaoling Yang ‡

¹Department of Endocrinology, The 980th (Bethune International Peace) Hospital of the Joint Logistic Support Force of PLA, China
Liye Hu ‡

¹Department of Endocrinology, The 980th (Bethune International Peace) Hospital of the Joint Logistic Support Force of PLA, China
Rui Han

²Department of Neurology, The First Affiliated Hospital of Hebei Medical University, China
Yiwen Yang

¹Department of Endocrinology, The 980th (Bethune International Peace) Hospital of the Joint Logistic Support Force of PLA, China

Abstract

A diabetic foot ulcer (DFU) is a serious complication in patients with diabetes mellitus (DM). A DFU is the most common cause of non-traumatic limb amputation, and patients with DFUs have increased mortality rates within 5 years after amputation. DFUs also increase the risk of cardiovascular and cerebrovascular diseases; therefore, with the increasing incidence and prevalence of diabetic foot wounds, DFUs are gradually becoming a major public health problem. The pathophysiology of DFUs is complicated and remains unclear. In recent years, many studies have demonstrated that the pathophysiology of DFUs is especially associated with neuropeptides, inflammation, and biofilms. Neuropeptides, especially substance P (SP) and calcitonin gene-related peptide (CGRP), play an important role in wound healing. SP and CGRP accelerate the healing of cutaneous wounds by promoting neovascularization, inhibiting the release of certain proinflammatory chemokines, regulating macrophage polarization, and so on. However, the expression of SP and CGRP was downregulated in DM and DFUs. DFUs are characterized by a sustained inflammatory phase. Immune cells such as neutrophils and macrophages are involved in the sustained inflammatory phase in DFUs by extracellular traps (NETs) and dysregulated macrophage polarization, which delays wound healing. Furthermore, DFUs are at increased risk of biofilm formation. Biofilms disturb wound healing by inducing a chronic inflammatory response, inhibiting macrophage phagocytosis and keratinocyte proliferation migration, and transferring antimicrobial resistance genes. To understand the relationships among neuropeptides, inflammation, biofilms, and DFUs, this review highlights the recent scientific advances that provide possible pathophysiological insights into the delayed healing of DFUs.

Full Text

References

References
1 Ogurtsova K, da Rocha Fernandes JD, Huang Y. et al. IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract 2017; 128: 40-50
2 Jeffcoate WJ, Macfarlane RM, Fletcher EM. The description and classification of diabetic foot lesions. Diabet Med 1993; 10: 676-679
3 Pradhan L, Nabzdyk C, Andersen ND. et al. Inflammation and neuropeptides: the connection in diabetic wound healing. Expert Rev Mol Med 2009; 11: e2
4 Wang LH, Zhou SX, Li RC. et al. Serum levels of calcitonin gene-related peptide and substance P are decreased in patients with diabetes mellitus and coronary artery disease. J Int Med Res 2012; 40: 134-140
5 Pradhan Nabzdyk L, Kuchibhotla S, Guthrie P. et al. Expression of neuropeptides and cytokines in a rabbit model of diabetic neuroischemic wound healing. J Vasc Surg 2013; 58: 766-775
6 Zhang Y, Chen Q, Sun Z. et al. Impaired capsaicin-induced relaxation in diabetic mesenteric arteries. J Diabetes Complications 2015; 29: 747-754
7 Liu D, Yang P, Gao M. et al. NLRP3 activation induced by neutrophil extracellular traps sustains inflammatory response in the diabetic wound. Clin Sci (Lond) 2019; 133: 565-582
8 Shapouri-Moghaddam A, Mohammadian S, Vazini H. et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol 2018; 233: 6425-6440
9 Wong SL, Demers M, Martinod K. et al. Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat Med 2015; 21: 815-819
10 Mirza R, Koh TJ. Dysregulation of monocyte/macrophage phenotype in wounds of diabetic mice. Cytokine 2011; 56: 256-264
11 Tankersley A, Frank MB, Bebak M. et al. Early effects of Staphylococcus aureus biofilm secreted products on inflammatory responses of human epithelial keratinocytes. J Inflamm (Lond) 2014; 11: 17
12 Gompelman M, van Asten SA, Peters EJ. Update on the Role of infection and biofilms in wound healing: pathophysiology and treatment. Plast Reconstr Surg 2016; 138: 61S-70S
13 Volmer-Thole M, Lobmann R. Neuropathy and diabetic foot syndrome. Int J Mol Sci 2016; 17
14 da Silva L, Carvalho E, Cruz MT. Role of neuropeptides in skin inflammation and its involvement in diabetic wound healing. Expert Opin Biol Ther 2010; 10: 1427-1439
15 Theocharidis G, Veves A. Autonomic nerve dysfunction and impaired diabetic wound healing: the role of neuropeptides. Auton Neurosci 2020; 223: 102610
16 Kim S, Piao J, Hwang DY. et al. Substance P accelerates wound repair by promoting neovascularization and preventing inflammation in an ischemia mouse model. Life Sci 2019; 225: 98-106
17 Kant V, Kumar D, Kumar D. et al. Topical application of substance P promotes wound healing in streptozotocin-induced diabetic rats. Cytokine 2015; 73: 144-155
18 Kant V, Kumar D, Prasad R. et al. Combined effect of substance P and curcumin on cutaneous wound healing in diabetic rats. J Surg Res 2017; 212: 130-145
19 Albiero M, Poncina N, Tjwa M. et al. Diabetes causes bone marrow autonomic neuropathy and impairs stem cell mobilization via dysregulated p66Shc and Sirt1. Diabetes 2014; 63: 1353-1365
20 Zhou J, Zhang Z, Qian G. Neuropathy and inflammation in diabetic bone marrow. Diabetes Metab Res Rev 2019; 35: e3083
21 Fadini GP, Albiero M, Vigili de Kreutzenberg S. et al. Diabetes impairs stem cell and proangiogenic cell mobilization in humans. Diabetes Care 2013; 36: 943-949
22 Park JH, Kim S, Hong HS. et al. Substance P promotes diabetic wound healing by modulating inflammation and restoring cellular activity of mesenchymal stem cells. Wound Repair Regen 2016; 24: 337-348
23 Um J, Jung N, Chin S. et al. Substance P enhances EPC mobilization for accelerated wound healing. Wound Repair Regen 2016; 24: 402-410
24 Okizaki S, Ito Y, Hosono K. et al. Suppressed recruitment of alternatively activated macrophages reduces TGF-beta1 and impairs wound healing in streptozotocin-induced diabetic mice. Biomed Pharmacother 2015; 70: 317-325
25 Miao M, Niu Y, Xie T. et al. Diabetes-impaired wound healing and altered macrophage activation: a possible pathophysiologic correlation. Wound Repair Regen 2012; 20: 203-213
26 Hesketh M, Sahin KB, West ZE. et al. Macrophage phenotypes regulate scar formation and chronic wound healing. Int J Mol Sci 2017; 18: 1545
27 Leal EC, Carvalho E, Tellechea A. et al. Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype. Am J Pathol 2015; 185: 1638-1648
28 Pradhan L, Cai X, Wu S. et al. Gene expression of proinflammatory cytokines and neuropeptides in diabetic wound healing. J Surg Res 2011; 167: 336-342
29 Ejaz A, LoGerfo FW, Khabbaz K. et al. Expression of neuropeptide Y, substance P, and their receptors in the right atrium of diabetic patients. Clin Transl Sci 2011; 4: 346-350
30 Mehta D, Granstein RD. Immunoregulatory effects of neuropeptides on endothelial cells: relevance to dermatological disorders. Dermatology 2019; 235: 175-186
31 Toda M, Suzuki T, Hosono K. et al. Roles of calcitonin gene-related peptide in facilitation of wound healing and angiogenesis. Biomed Pharmacother 2008; 62: 352-359
32 Mishima T, Ito Y, Hosono K. et al. Calcitonin gene-related peptide facilitates revascularization during hindlimb ischemia in mice. Am J Physiol Heart Circ Physiol 2011; 300: H431-H439
33 Mapp PI, McWilliams DF, Turley MJ. et al. A role for the sensory neuropeptide calcitonin gene-related peptide in endothelial cell proliferation in vivo. Br J Pharmacol 2012; 166: 1261-1271
34 Huang J, Stohl LL, Zhou X. et al. Calcitonin gene-related peptide inhibits chemokine production by human dermal microvascular endothelial cells. Brain Behav Immun 2011; 25: 787-799
35 Zhang X, Zhuang J, Wu H. et al. Inhibitory effects of calcitonin gene-related peptides on experimental vein graft disease. Ann Thorac Surg 2010; 90: 117-123
36 Duan JX, Zhou Y, Zhou AY. et al. Calcitonin gene-related peptide exerts anti-inflammatory property through regulating murine macrophages polarization in vitro. Mol Immunol 2017; 91: 105-113
37 Roggenkamp D, Kopnick S, Stab F. et al. Epidermal nerve fibers modulate keratinocyte growth via neuropeptide signaling in an innervated skin model. J Invest Dermatol 2013; 133: 1620-1628
38 Enriquez-Perez IA, Galindo-Ordonez KE, Pantoja-Ortiz CE. et al. Streptozocin-induced type-1 diabetes mellitus results in decreased density of CGRP sensory and TH sympathetic nerve fibers that are positively correlated with bone loss at the mouse femoral neck. Neurosci Lett 2017; 655: 28-34
39 Roth Flach RJ, Czech MP. NETs and traps delay wound healing in diabetes. Trends Endocrinol Metab 2015; 26: 451-452
40 Fadini GP, Menegazzo L, Rigato M. et al. NETosis delays diabetic wound healing in mice and humans. Diabetes 2016; 65: 1061-1071
41 Yang S, Gu Z, Lu C. et al. Neutrophil extracellular traps are markers of wound healing impairment in patients with diabetic foot ulcers treated in a multidisciplinary setting. Adv Wound Care (New Rochelle) 2020; 9: 16-27
42 Hudock KM, Collins MS, Imbrogno M. et al. Neutrophil extracellular traps activate IL-8 and IL-1 expression in human bronchial epithelia. Am J Physiol Lung Cell Mol Physiol 2020; 319: L137-L147
43 Siqueira MF, Li J, Chehab L. et al. Impaired wound healing in mouse models of diabetes is mediated by TNF-alpha dysregulation and associated with enhanced activation of forkhead box O1 (FOXO1). Diabetologia 2010; 53: 378-388
44 Ashcroft GS, Jeong MJ, Ashworth JJ. et al. Tumor necrosis factor-alpha (TNF-alpha) is a therapeutic target for impaired cutaneous wound healing. Wound Repair Regen 2012; 20: 38-49
45 Huang SM, Wu CS, Chiu MH. et al. High glucose environment induces M1 macrophage polarization that impairs keratinocyte migration via TNF-alpha: An important mechanism to delay the diabetic wound healing. J Dermatol Sci 2019; 96: 159-167
46 Basso FG, Pansani TN, Turrioni AP. et al. Tumor necrosis factor-alpha and interleukin (IL)-1beta, IL-6, and IL-8 impair in vitro migration and induce apoptosis of gingival fibroblasts and epithelial cells, delaying wound healing. J Periodontol 2016; 87: 990-996
47 Yan C, Gao N, Sun H. et al. Targeting imbalance between IL-1beta and IL-1 receptor antagonist ameliorates delayed epithelium wound healing in diabetic mouse corneas. Am J Pathol 2016; 186: 1466-1480
48 Johnson BZ, Stevenson AW, Prele CM. et al. The role of IL-6 in skin fibrosis and cutaneous wound healing. Biomedicines 2020; 8: 101
49 Dinh T, Tecilazich F, Kafanas A. et al. Mechanisms involved in the development and healing of diabetic foot ulceration. Diabetes 2012; 61: 2937-2947
50 Weigelt C, Rose B, Poschen U. et al. Immune mediators in patients with acute diabetic foot syndrome. Diabetes Care 2009; 32: 1491-1496
51 Ahmad J, Zubair M, Malik A. et al. Cathepsin-D, adiponectin, TNF-alpha, IL-6 and hsCRP plasma levels in subjects with diabetic foot and possible correlation with clinical variables: a multicentric study. Foot (Edinb) 2012; 22: 194-199
52 Zubair M, Malik A, Ahmad J. Plasma adiponectin, IL-6, hsCRP, and TNF-alpha levels in subject with diabetic foot and their correlation with clinical variables in a North Indian tertiary care hospital. Indian J Endocrinol Metab 2012; 16: 769-776
53 Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 2012; 122: 787-795
54 He R, Yin H, Yuan B. et al. IL-33 improves wound healing through enhanced M2 macrophage polarization in diabetic mice. Mol Immunol 2017; 90: 42-49
55 Montanaro M, Meloni M, Anemona L. et al. Macrophage activation and M2 polarization in wound bed of diabetic patients treated by dermal/epidermal substitute nevelia. Int J Low Extrem Wounds 2020; 1534734620945559
56 Khanna S, Biswas S, Shang Y. et al. Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice. PLoS One 2010; 5: e9539
57 Bannon P, Wood S, Restivo T. et al. Diabetes induces stable intrinsic changes to myeloid cells that contribute to chronic inflammation during wound healing in mice. Dis Model Mech 2013; 6: 1434-1447
58 Grigoropoulou P, Eleftheriadou I, Jude EB. et al. Diabetic Foot infections: an update in diagnosis and management. Curr Diab Rep 2017; 17: 3
59 Alavi A, Sibbald RG, Mayer D. et al. Diabetic foot ulcers: Part II. Management. J Am Acad Dermatol 2014; 70: 21 e21-e24
60 Al-Joufi FA, Aljarallah KM, Hagras SA. et al. Microbial spectrum, antibiotic susceptibility profile, and biofilm formation of diabetic foot infections (2014–18): a retrospective multicenter analysis. 3 Biotech 2020; 10: 325
61 Clinton A, Carter T. Chronic wound biofilms: pathogenesis and potential therapies. Lab Med 2015; 46: 277-284
62 Banu A, Noorul Hassan MM, Rajkumar J. et al. Spectrum of bacteria associated with diabetic foot ulcer and biofilm formation: a prospective study. Australas Med J 2015; 8: 280-285
63 Mottola C, Mendes JJ, Cristino JM. et al. Polymicrobial biofilms by diabetic foot clinical isolates. Folia Microbiol (Praha) 2016; 61: 35-43
64 Vatan A, Saltoglu N, Yemisen M. et al. Association between biofilm and multi/extensive drug resistance in diabetic foot infection. Int J Clin Pract 2018; 72: e13060
65 Arima S, Ochi H, Mitsuhashi M. et al. Staphylococcus pseudintermedius biofilms secrete factors that induce inflammatory reactions in vitro. Lett Appl Microbiol 2018; 67: 214-219
66 Arce Miranda JE, Baronetti JL, Sotomayor CE. et al. Oxidative and nitrosative stress responses during macrophage-Candida albicans biofilm interaction. Med Mycol 2019; 57: 101-113
67 Scherr TD, Hanke ML, Huang O. et al. Staphylococcus aureus biofilms induce macrophage dysfunction through leukocidin AB and Alpha-Toxin. mBio 2015; 6: e01021-15
68 Schierle CF, De la Garza M, Mustoe TA. et al. Staphylococcal biofilms impair wound healing by delaying reepithelialization in a murine cutaneous wound model. Wound Repair Regen 2009; 17: 354-359
69 Jeffery Marano R, Jane Wallace H, Wijeratne D. et al. Secreted biofilm factors adversely affect cellular wound healing responses in vitro. Sci Rep 2015; 5: 13296
70 Trostrup H, Lerche CJ, Christophersen LJ. et al. Pseudomonas aeruginosa biofilm hampers murine central wound healing by suppression of vascular epithelial growth factor. Int Wound J 2018; 15: 123-132