Myeloid Cell–Restricted Insulin/IGF-1 Receptor Deficiency Protects against Skin Inflammation

Abstract

Myeloid cells are key regulators of tissue homeostasis and disease. Alterations in cell-autonomous Insulin/IGF-1 signaling in myeloid cells have recently been implicated in the development of systemic inflammation and insulin-resistant diabetes mellitus type 2 (DM). Impaired wound healing and inflammatory skin diseases are frequent DM-associated skin pathologies, yet the underlying mechanisms are elusive. Here we investigated whether myeloid cell-restricted IR/IGF-1R signalling provides a pathophysiological link between systemic insulin resistance and the development of cutaneous inflammation. Therefore, we generated mice lacking both the Insulin and IGF-1 receptor in myeloid cells (IR/IGF-1RMKO). Whereas the kinetics of wound closure following acute skin injury was similar in control and IR/IGF-1RMKO mice, in two different conditions of dermatitis either induced by repetitive topical applications of the detergent SDS or by high-dose UVB radiation, IR/IGF-1RMKO mice were protected from inflammation, whereas controls developed severe skin dermatitis. Notably, whereas during the early phase in both inflammatory conditions the induction of epidermal pro-inflammatory cytokine expression was similar in control and IR/IGF-1RMKO mice, during the late stage, epidermal cytokine expression was sustained in controls, however virtually abrogated in IR/IGF-1RMKO mice. This distinct kinetic of epidermal cytokine expression was paralleled by pro-inflammatory macrophage activation in controls and a non-inflammatory phenotype in mutants. Collectively, our findings provide evidence for a pro-inflammatory IR/IGF-1R-dependent pathway in myeloid cells that plays a critical role in the dynamics of an epidermal-dermal crosstalk in cutaneous inflammatory responses, and may add to the mechanistic understanding of diseases associated with disturbances in myeloid cell IR/IGF-1R signaling including DM.

Role of Insulin-Like Growth Factor Binding Protein-3 in the Pathogenesis of Herpes Stromal Keratitis

“…IGFBP-3 in the IGF independent manner is reported to induce the cellular senescence, 51 and the latter is shown to reduce the viral load. 52 Besides, IGFBP-3 also regulates IGF-1R mediated signaling in macrophages, 53 and the latter immune cell type is involved in regulating the establishment of HSV-1 latency in the trigeminal ganglia. 7,54 Thus, IGFBP-3 in an IGF-dependent or independent manner may participate in regulating viral load in the cornea and trigeminal ganglia of HSV-1 infected mice.…”

Macrophages in Tissue Repair, Regeneration, and Fibrosis

“…In addition to communicating anti-inflammatory signals directly to epithelial cells, macrophages also regulate communication in the epidermis. Knuever and colleagues have shown that myeloid cell-restricted insulin and IGF-1 receptor deficiency protects mice from skin inflammation by decreasing pro-inflammatory cytokine production from epidermal cells (Knuever et al, 2015). Monocyte and macrophage-derived IGF-1 has also been identified as a critical factor in skeletal muscle repair (Tonkin et al, 2015).…”

Insulin Signaling and Insulin Resistance Facilitate Trained Immunity in Macrophages Through Metabolic and Epigenetic Changes

“…Resident macrophages obtain M1 or M2 phenotypes, depending on the microenvironment and the stimuli present, such as this of insulin that induces AKT kinase signals (3, 41). In the context of insulin resistance, peripheral macrophages acquire an anti-inflammatory M2-like phenotype, characterized by increased expression of M2 markers and reduced secretion of pro-inflammatory factors upon stimulation (3, 42). In addition, insulin resistant macrophages produce reduced levels of NO upon TLR stimulation in vivo and in culture and exhibit reduced bactericidal capacity in vivo (3).…”