The Transcriptional Activation Program of Human Neutrophils in Skin Lesions Supports Their Important Role in Wound Healing

Abstract

To investigate the cellular fate and function of polymorphonuclear neutrophilic granulocytes (PMNs) attracted to skin wounds, we used a human skin-wounding model and microarray technology to define differentially expressed genes in PMNs from peripheral blood, and PMNs that had transmigrated to skin lesions. After migration to skin lesions, PMNs demonstrated a significant transcriptional response including genes from several different functional categories. The up-regulation of anti-apoptotic genes concomitant with the down-regulation of proapoptotic genes suggested a transient anti-apoptotic priming of PMNs. Among the up-regulated genes were cytokines and chemokines critical for chemotaxis of macrophages, T cells, and PMNs, and for the modulation of their inflammatory responses. PMNs in skin lesions down-regulated receptors mediating chemotaxis and anti-microbial activity, but up-regulated other receptors involved in inflammatory responses. These findings indicate a change of responsiveness to chemotactic and immunoregulatory mediators once PMNs have migrated to skin lesions and have been activated. Other effects of the up-regulated cytokines/chemokines/enzymes were critical for wound healing. These included the breakdown of fibrin clots and degradation of extracellular matrix, the promotion of angiogenesis, the migration and proliferation of keratinocytes and fibroblasts, the adhesion of keratinocytes to the dermal layer, and finally, the induction of anti-microbial gene expression in keratinocytes. Notably, the up-regulation of genes, which activate lysosomal proteases, indicate a priming of skin lesion-PMNs for degradation of phagocytosed material. These findings demonstrate that migration of PMNs to skin lesions induces a transcriptional activation program, which regulates cellular fate and function, and promotes wound healing.

Omega 3 fatty acids supplementation has an ameliorative effect in experimental ulcerative colitis despite increased colonic neutrophil infiltration

“…Neutrophils are thought to play a negative role in normal tissue repair as they produce bioactive substances capable of accelerating tissue damage (25), including oxygen radicals (26), digestive enzymes and proinflammatory cytokines (27). However, recent studies have shown that neutrophils may play a beneficial role in wound healing and tissue remodeling and also may have anti-inflammatory properties (28)(29)(30)(31)(32)(33)(34). Neutrophils are considered necessary for early steps in wound healing based on the finding that the depletion of neutrophils dramatically delayed wound healing (28).…”

“…Moreover neutrophil recruitment is considered to play an important role in ulcer healing based on the finding that the recruitment of neutrophils to the ulcer site was associated with elevated mucus secretion, thicker regenerative gastric mucosa and increased cell proliferation in an experimental model of acetic acid-induced gastric ulcers (30). Furthermore, neutrophils upregulate VEGF, IL-8, growth-related oncogene (GRO)-γ and MCP-1 cytokines, which have been reported to stimulate the growth of endothelial cells and fibroblasts (31), and also neutrophils synthesize significant levels of anti-inflammatory mediators, including cytokine inhibitors such as type 2 TNF soluble receptor and IL-1 receptor antagonist in experimental models (32). Moreover, another study demonstrated the production of the IL-1 receptor antagonist, but not the production of pro-inflammatory cytokines TNFα, IL-1β and IL-6 (33).…”

Changing world of neutrophils

“…Determination of the gene expression profile of neutrophils from the bone marrow, circulating blood or a skin lesion of mice indicated that transmigration through the vessel wall initiates a new transcription program leading to the synthesis of regulatory and cell-fate determining proteins [11,105,106]. Phagocytosis of opsonized particles via Fc and/or complement receptors also altered the expression of numerous genes, many of them affecting proteins involved in apoptotic pathways [56,57].…”

Leukocyte Function in High-Flux Hemodialysis

“…by interacting with immune modulating cells Yamashiro et al 2001;Cohen et al 2003;Theilgaard-Monch et al 2004). Neutrophil cytokine and chemokine production can be an important link between the innate and the adaptive immune responses.…”