Chronic Inflammation in Response to Injury: Retention of Myeloid Cells in Injured Tissue Is Driven by Myeloid Cell Intrinsic Factors

Abstract

Chronic inflammation is a hallmark of impaired healing in a plethora of tissues, including skin, and is associated with aging and diseases such as diabetes. Diabetic chronic skin wounds are characterized by excessive myeloid cells that display an aberrant phenotype, partially mediated by stable intrinsic changes induced during hematopoietic development. However, the relative contribution of myeloid celleintrinsic factors to chronic inflammation versus aberrant signals from the local environmental was unknown. Moreover, identification of myeloid cell intrinsic factors that contribute to chronic inflammation in diabetic wounds remained elusive. Here we show that Gr-1 þ CD11b þ myeloid cells are retained specifically within the presumptive granulation tissue region of the wound at a higher density in diabetic mice and associate with endothelial cells at the site of injury with a higher frequency than in nondiabetic mice. Adoptive transfer of myeloid cells demonstrated that aberrant wound retention is due to myeloid cell intrinsic factors and not the local environment. RNA sequencing of bone marrow and wound-derived myeloid cells identified Selplg as a myeloid cell intrinsic factor that is deregulated in chronic wounds. In vivo blockade of this protein significantly accelerated wound healing in diabetic mice and may be a potential therapeutic target in chronic wounds and other chronic inflammatory diseases.

Cx3CR1 Expression Identifies Distinct Macrophage Populations That Contribute Differentially to Inflammation and Repair

“…In recruited inflammatory cells this has been linked to an immaturity phenotype (6), but our results suggest this does not appear to be the case with the tissue-resident macrophages. However, prepriming of resident macrophages from continuous exposure to inflammatory cytokines prior to injury may underlie their altered responses as it does for BM-derived myeloid cells (7). Further investigation into the molecular mechanisms contributing to altered resident macrophage responses in diabetes should address these issues.…”

“…Current therapies for chronic diabetic wounds primarily target the symptoms of the diabetic changes in wound pathology, with poor healing outcomes in many patients (2). To better understand the etiology behind diabetic wounds there has been much focus upon the role of inflammatory cell populations within the wound environment and how they may be altered in diabetes (3)(4)(5)(6)(7).…”

“…There is also evidence for diabetes altering the number or phenotype of nonlassical monocytes in humans (30)(31)(32). Together with diabetes-induced changes in other myeloid cell lineages such as neutrophils (7), macrophages drive the elevated, nonresolving inflammatory state of chronic nonhealing diabetic wounds (33)(34)(35).…”

Emerging Roles of Myeloid-Derived Suppressor Cells in Diabetes

“…Human umbilical cord mesenchymal stem cells (Huc-MSCs), which are widely used in NOD mice, can inhibit the differentiation of MDSC by secreting the soluble factors COX2/PGE2 and IFN-β and enhance their inhibitory ability on immune cells so as to achieve effective therapeutic effects against diabetes ( Qi et al, 2020 ). Based on the aforementioned findings, the metastasis of MDSC, f-MDSC, or the transfer of Huc-MSCs may possess the enhanced inhibitory ability on immunity and demonstrate the therapeutic effect on diabetic mice ( Yin et al, 2010 ; Xia et al, 2011 ; Torbica et al, 2019 ; Ren et al, 2021 ). MDSC-related stem cells also may be a promising treatment for diabetes.…”

Stat3 oxidation-dependent regulation of gene expression impacts on developmental processes and involves cooperation with Hif-1α

“…Although participation of both redox signalling and Stat3 in inflammatory responses is well established [53,54], the link between Stat3 oxidation and up-regulation of genes encoding immune regulators is new. For example, cluster 1,0,0,-1, which defines genes that are acutely sensitive to peroxide, is enriched for components of humoral and adaptive immune responses, such as Foxj1 (6.6-fold), a regulator of T cell activation [55]; Selplg (10.4-fold), a promoter of myeloid cell recruitment [56]; Hpx (5.6-fold), a haem scavenger and suppressor of ROS-mediated macrophage activation [57]. Also up-regulated in peroxide-stimulated -/-WT cells are genes for Gpr15L (2610528A11Rik, 14.6-fold), recently implicated in T cell responses to epithelial damage [58] and Nlrp3 (~30-fold), eponymous component of the ROS-inducible Nlrp3 inflammasome [59].…”