Innate Immunity in Diabetic Wound Healing: Focus on the Mastermind Hidden in Chronic Inflammatory

Abstract

A growing body of evidence suggests that the interaction between immune and metabolic responses is essential for maintaining tissue and organ homeostasis. These interacting disorders contribute to the development of chronic diseases associated with immune-aging such as diabetes, obesity, atherosclerosis, and nonalcoholic fatty liver disease. In Diabetic wound (DW), innate immune cells respond to the Pathogen-associated molecular patterns (PAMAs) and/or Damage-associated molecular patterns (DAMPs), changes from resting to an active phenotype, and play an important role in the triggering and maintenance of inflammation. Furthermore, the abnormal activation of innate immune pathways secondary to immune-aging also plays a key role in DW healing. Here, we review studies of innate immune cellular molecular events that identify metabolic disorders in the local microenvironment of DW and provide a historical perspective. At the same time, we describe some of the recent progress, such as TLR receptor-mediated intracellular signaling pathways that lead to the activation of NF-κB and the production of various pro-inflammatory mediators, NLRP3 inflammatory via pyroptosis, induction of IL-1β and IL-18, cGAS-STING responds to mitochondrial injury and endoplasmic reticulum stress, links sensing of metabolic stress to activation of pro-inflammatory cascades. Besides, JAK-STAT is also involved in DW healing by mediating the action of various innate immune effectors. Finally, we discuss the great potential of targeting these innate immune pathways and reprogramming innate immune cell phenotypes in DW therapy.

Relevance of NLRP3 Inflammasome-Related Pathways in the Pathology of Diabetic Wound Healing and Possible Therapeutic Targets

“…M φ derived from monocytes participates in each phase of the wound healing process because they kill pathogenic microbes, remove damaged tissue, and produce growth factors [ 48 ]. In response to complex microenvironments and molecular mediators, M φ is polarized into the classical pr-inflammatory M1 or alternative anti-inflammatory M2 [ 49 ]. The orderly transition from M1 to M2 results in beneficial effects on wound healing, particularly in tissue remodeling and angiogenesis [ 50 ].…”

“…In the DW state, chronic low-grade inflammation that persists indefinitely is a key cause of nonhealing of wounds [ 52 ], wherein M1 persists continuously and cannot transit to M2 phenotypes. In addition, Ganesh et al [ 53 ] found that the levels of proinflammatory cytokines, including interleukin-1 beta (IL-1 β ), tumor necrosis factor-alpha (TNF- α ), and interferon-gamma (IFN- γ ), are elevated in DW, which induces local hyperglycemia, accumulation of advanced glycation end products (AGEs), and ROS, along with an increase in chronic inflammation [ 49 ]. The same outcome has been observed in animal experiments, in which macrophages from normal mice switched from a pro- to anti-inflammatory phenotype on the tenth day, while diabetic mice displayed a twofold higher expression of proinflammatory factors IL-1 β and IFN- γ [ 54 ], which facilitated the maintenance of the proinflammatory M1 phenotype.…”

The Role of microRNA in the Inflammatory Response of Wound Healing

“…The injury leads to the activation of the coagulation system, which successfully stops bleeding and provides the necessary matrix for the initiation of the inflammatory response. Tissue-resident cell surface pattern recognition receptors (PRRs) are recognized by Damage Associated Molecular Patterns (DAMPs) or Pathogen Associated Molecular Patterns (PAMPs), which in turn release specific chemokines and pro-inflammatory cytokines to recruit inflammatory cells ( 13 ). At the same time, the intracellular inflammatory signaling pathways, such as toll-like receptors (TLRs) and nuclear factor kappa B (NFκB) at the wound site are activated to trigger a signaling cascade ( 14 ).…”

New Insights on the Effects of Dietary Omega-3 Fatty Acids on Impaired Skin Healing in Diabetes and Chronic Venous Leg Ulcers

“…Over the last two decades, a wide body of literature has explored the mechanisms underlying the impaired WH occurring in both of these pathologic conditions. This has led to the identification of alterations in cells, cellular functions, molecular pathways, and molecules involved, all representing potential targets of innovative therapeutic strategies [79,80]. In particular, the prevailing current approach in studying the mechanisms underlying the physiological and pathological WH processes is that of focusing on the types/subtypes and functions of cells recruited or participating in the development and termination of the processes [17], as well as their possible qualitative or quantitative modifications leading to WH impairment and delay.…”