Epigenetic Regulation of TLR4 in Diabetic Macrophages Modulates Immunometabolism and Wound Repair

Fm, Davis; denDekker, Aaron D.; Kimball, Andrew; Joshi, Avani; M, El Azzouny; Sj, Wolf; Obi, Andrea; Lipinski, Jay H; Gudjonsson, Johann E.; Xing, Xianying; Plazyo, Olesya; Audu, Christopher O.; Wj, Melvin; K, Singer; Pk, Henke; Moore, BB; Burant, Charles F.; Sl, Kunkel; Ka, Gallagher

doi:10.4049/jimmunol.1901263

Cited by 26 publications

(24 citation statements)

References 68 publications

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“…In general support of this idea, the principal component of LPS responsible for its immunostimulatory activity is the lipid A region, which contains numerous saturated fatty acyl chains that are required for binding to and activating TLR4. Importantly, consistent with this previous work, we observed a protective effect of TLR4 deficiency on SFA induced macrophage activation in two independent loss-offunction models, Tlr4 −/− mice and MyD88 −/− mice [35]. Despite progress of these previous studies, the precise downstream mechanism by which the TLR4 pathway contributes to chronic macrophage inflammation remains unknown.…”

Section: Discussionsupporting

confidence: 90%

Palmitate‐TLR4 signaling regulates the histone demethylase, JMJD3, in macrophages and impairs diabetic wound healing

et al. 2020

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Chronic macrophage inflammation is a hallmark of type 2 diabetes (T2D) and linked to the development of secondary diabetic complications. T2D is characterized by excess concentrations of saturated fatty acids (SFA) that activate innate immune inflammatory responses, however, mechanism(s) by which SFAs control inflammation is unknown. Using monocyte-macrophages isolated from human blood and murine models, we demonstrate that palmitate (C16:0), the most abundant circulating SFA in T2D, increases expression of the histone demethylase, Jmjd3. Upregulation of Jmjd3 results in removal of the repressive histone methylation (H3K27me3) mark on NFκB-mediated inflammatory gene promoters driving macrophage-mediated inflammation. We identify that the effects of palmitate are fatty acid specific, as laurate (C12:0) does not regulate Jmjd3 and the associated inflammatory profile. Further, palmitate-induced Jmjd3 expression is controlled via TLR4/MyD88-dependent signaling mechanism, where genetic depletion of TLR4 (Tlr4 −/−) or MyD88 (MyD88 −/−) negated the palmitate-induced changes in Jmjd3 and downstream NFκB-induced inflammation. Pharmacological inhibition of Jmjd3 using a small molecule inhibitor (GSK-J4) reduced macrophage inflammation and improved diabetic wound healing. Together, we conclude that palmitate contributes to the chronic Jmjd3-mediated activation of macrophages in diabetic peripheral tissue and a histone demethylase inhibitor-based therapy may represent a novel treatment for nonhealing diabetic wounds.

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Section: Discussionsupporting

confidence: 90%

Palmitate‐TLR4 signaling regulates the histone demethylase, JMJD3, in macrophages and impairs diabetic wound healing

et al. 2020

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“…Activation of the TLR4 signalling pathway increases TLR4 surface expression in macrophages, and Flii negatively regulates this TLR4 signalling pathway [ 2 , 4 , 16 ]. To determine whether altering Flii levels modifies TLR4 surface expression on macrophages, mouse peritoneal macrophages were obtained from 3 Flii genotypes, Flightless heterozygous (Flii +/− , 50% levels of Flii), wildtype BALB/C (WT, 100% levels of Flii), and Flightless transgenic (Flii Tg/Tg , 150% levels of Flii) [ 24 ].…”

Section: Resultsmentioning

confidence: 99%

“…A mounting body of evidence suggests that TLR4-regulated inflammation is important for a timely repair process, specifically TLR4 on the surface of macrophages [ 2 , 3 , 4 , 6 , 28 , 29 ]. Both Flii and TLR4 are temporally upregulated during wound healing [ 3 , 6 , 12 , 13 ].…”

Section: Discussionmentioning

confidence: 99%

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Flightless I Negatively Regulates Macrophage Surface TLR4, Delays Early Inflammation, and Impedes Wound Healing

Mills

Ahangar

Thomas

et al. 2022

Cells

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TLR4 plays a pivotal role in orchestrating inflammation and tissue repair. Its expression has finally been balanced to initiate the early, robust immune response necessary for efficient repair without excessively amplifying and prolonging inflammation, which impairs healing. Studies show Flightless I (Flii) is an immunomodulator that negatively regulates macrophage TLR4 signalling. Using macrophages from Flii+/−, WT, and FliiTg/Tg mice, we have shown that elevated Flii reduces early TLR4 surface expression, delaying and reducing subsequent TNF secretions. In contrast, reduced Flii increases surface TLR4, leading to an earlier robust TNF peak. In Flii+/− mice, TLR4 levels peak earlier during wound repair, and overall healing is accelerated. Fewer neutrophils, monocytes and macrophages are recruited to Flii+/− wounds, leading to fewer TNF-positive macrophages, alongside an early peak and a robust shift to M2 anti-inflammatory, reparative Ym1+ and IL-10+ macrophages. Importantly, in diabetic mice, high Flii levels are found in plasma and unwounded skin, with further increases observed in their wounds, which have impaired healing. Lowering Flii in diabetic mice results in an earlier shift to M2 macrophages and improved healing. Overall, this suggests Flii regulation of TLR4 reduces early inflammation and decreases the M2 macrophage phenotype, leading to impaired healing.

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“…Further, Histone methylation can also alter the Mp phenotype to affect DW healing (Boniakowski et al, 2017). For example, MLL1-mediated epigenetic alterations activated H3K4me3-TLR4-MyD88, use TLR4 inhibitor TAK-242 as well as genetic depletion of either TLR4 −/− or myeloidspecific TLR4 f/f Lyz2 Cre+ resulted in a reduction in Mp-mediated inflammation and improved DW healing (Davis et al, 2020). In another study, the decreased expression of H3K27me3 corresponds Varol et al (2007), Yona et al (2013) 3.Die in the wound during the inflammatory, repair, proliferation period Albina et al (1990) 4.Enter the non-lymphoid organs and circulated to the lymph nodes Jakubzick et al to the increased Jmjd3 and IL12 expression promoting the exaggerated pro-inflammatory response seen in diabetic Mp (Gallagher et al, 2015).…”

Section: Spatial and Temporal Expression Difference Of Monocytes Is A Double-edged Sword For Diabetic Wound Healingmentioning

confidence: 99%

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

Geng

Jiang³

et al. 2021

Front. Pharmacol.

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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.

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Epigenetic Regulation of TLR4 in Diabetic Macrophages Modulates Immunometabolism and Wound Repair

Cited by 26 publications

References 68 publications

Palmitate‐TLR4 signaling regulates the histone demethylase, JMJD3, in macrophages and impairs diabetic wound healing

Palmitate‐TLR4 signaling regulates the histone demethylase, JMJD3, in macrophages and impairs diabetic wound healing

Flightless I Negatively Regulates Macrophage Surface TLR4, Delays Early Inflammation, and Impedes Wound Healing

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

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