Macrophage‐derived HMGB1 is dispensable for tissue fibrogenesis

Abstract

Alarmins and damage‐associated molecular patterns (DAMPs) are powerful inflammatory mediators, capable of initiating and maintaining sterile inflammation during acute or chronic tissue injury. Recent evidence suggests that alarmins/DAMPs may also trigger tissue regeneration and repair, suggesting a potential contribution to tissue fibrogenesis. High mobility group B1 (HMGB1), a bona fide alarmin/DAMP, may be released passively by necrotic cells or actively secreted by innate immune cells. Macrophages can release large amounts of HMGB1 and play a key role in wound healing and regeneration processes. Here, we hypothesized that macrophages may be a key source of HMGB1 and thereby contribute to wound healing and fibrogenesis. Surprisingly, cell‐specific deletion approaches, demonstrated that macrophage‐derived HMGB1 is not involved in tissue fibrogenesis in multiple organs with different underlying pathologies. Compared to control HMGB1Flox mice, mice with macrophage‐specific HMGB1 deletion (HMGB1ΔMac) do not display any modification of fibrogenesis in the liver after CCL4 or thioacetamide treatment and bile duct ligation; in the kidney following unilateral ureter obstruction; and in the heart after transverse aortic constriction. Of note, even under thermoneutral housing, known to exacerbate inflammation and fibrosis features, HMGB1ΔMac mice do not show impairment of fibrogenesis. In conclusion, our study clearly establishes that macrophage‐derived HMGB1 does not contribute to tissue repair and fibrogenesis.

Glycyrrhizic acid, as an inhibitor of HMGB1, alleviates bleomycin-induced pulmonary toxicity in mice through the MAPK and Smad3 pathways

“…[18][19][20]. Moreover, HMGB1 can not only act as a proinflammatory factor to directly involve in tissue damage [21,22], but also HMGB1 can induce lung fibrosis through NF-jBmediated TGF-b1 release because HMGB1 knockdown significantly suppress TGF-b1-induced a-SMA and collagen protein expression [23], which is consistent with our results, TGF-b1 and SMA expression were decreased after HMGB1 inhibition (Figure 3).…”

Thermoneutrality and Immunity: How Does Cold Stress Affect Disease?

“…Some immune factors, such as TNF-a, Il-6, and Il-1b, have been implicated in the differential response to immune challenge at TT compared to ST due to their function as pyrogens in the fever response (27,41,43). In addition, high mobility group box 1 (HMGB1), the macrophage-derived factor involved in tissue repair and tissue fibrosis, was found at a higher level in circulation at TT and higher liver inflammation was observed (44). Interestingly, immune-challenged rodents tend to prefer environmental temperatures closer to their TT, indicating that TT is beneficial in the response to various pathogens (40).…”

“…Thermoneutrality also has an effect on obesity-related disease presentations such as atherosclerosis and non-alcoholic fatty liver disease (NAFLD) (44,51,52,83). Atherosclerosis is defined as plaque build-up coupled with immune cell infiltration in the blood vessel wall and is one of the leading causes of cardiovascular disease (CVD) (83).…”

“…It occurs when there is an increase of lipids in the circulation as a result of changes in the metabolic environment (83). When housed at TT, mice display two metabolic markers of atherosclerosis (i.e., adipose and vasculature inflammation) faster than at ST, even if there is no change in insulin resistance (44,51). Macrophage infiltration in the aorta and upregulation of pro-inflammatory cytokines, chemokines and other inflammatory mediators were observed at TT (51).…”

“…Oxygen consumption was unaffected at TT for mice but decreased for rats (86). These changes can predispose rodents to cardiovascular events like coronary artery disease or atherosclerosis, described in the Metabolic Diseases section (44,51). It is not yet clear whether TN has a protective effect on other CVDs.…”