InVivoMAb anti-mouse IL-18

Metabolic-inflammatory crosstalk orchestrates muscle repair. Although pyroptosis typically aggravates sterile injury, we demonstrated that GSDME-dependent pyroptotic signaling associated with recruited myeloid cells paradoxically supported regeneration. GSDME expression was induced in postsurgical human muscle injury and murine damage models. Gsdme deficiency delayed functional recovery and exacerbated injury-induced myosteatosis, a pathological form of intramuscular ectopic fat deposition. Time-series and scRNA-seq analyses revealed that GSDME loss shifted the transcriptional program from oxidative metabolism to lipid storage and adipogenesis. Lipidomics confirmed aberrant accumulation of triacylglycerols (TAGs) and sphingolipids in Gsdme-deficient muscle. Single-cell profiling further identified divergent fibro-adipogenic progenitor (FAP) states skewed toward adipogenesis, accompanied by impaired expansion of restorative Lyve1+Cd163+Txnip+ tissue-resident macrophages (TRMs), as validated by multiplex flow cytometry. Blocking CCR2-dependent monocyte recruitment produced regenerative defects comparable with those caused by Gsdme deficiency. Myeloid-specific Gsdme reintroduction rescued TRM expansion and function and curbed FAP adipogenic reprogramming, whereas FAP-specific expression proved ineffective. Mechanistically, IL-18 downstream of GSDME-dependent signaling engaged KLF4/JUN signaling in TRMs, sustaining their reparative and lipid-clearing capacity. This GSDME-IL-18-TRM axis was compromised in aged muscle, yet exogenous IL-18 reversed myosteatosis and accelerated regeneration. Together, these findings suggest that GSDME-dependent pyroptotic signaling can act as a metabolic checkpoint that sustains TRM-driven lipid homeostasis to support muscle regeneration.

A growing consensus indicates that periodontitis (PD) adversely affects glycemic control in type 2 diabetes, though its underlying mechanisms remain unclear. Here, we report that PD, induced by long-term oral ligatures, significantly aggravated hyperglycemia and hepatic gluconeogenesis in high-fat diet-induced obese mice, with its impact on insulin resistance being more pronounced in the liver than in adipose or muscle tissue. Immunologically, PD increased systemic B cell abundance, promoted hepatic B2 cell mobilization, facilitated the expansion of Kupffer cells and adipose tissue macrophages, and activated the NLRP3 inflammasome. Depleting B cells significantly alleviated PD-induced glucose dysregulation, whereas adoptive transfer of B cells from PD mice exacerbated glucose dysregulation and Kupffer cell expansion in Rag1-/- mice. Mechanistically, upregulation of the interleukin (IL)-18 receptor was observed in PD-exposed B cells. IL-18 directly enhanced B cell proliferation, and hepatic macrophages from PD mice secreted elevated levels of IL-18, further driving B cell expansion. Neutralizing IL-18 or depleting macrophages significantly mitigated PD-associated metabolic and B cell abnormalities. Therefore, PD exacerbates hyperglycemia by promoting the pathogenic expansion of B cells and their crosstalk with macrophages via the IL-18 signaling axis. Targeting the NLRP3/IL-18 axis holds promise for preventing glucose dysregulation and aberrant immune cell interactions primed by PD.

Many molecular mechanisms underlying tumor escape, in which cancer cells undergo epithelial-to-mesenchymal transition (EMT) and thereby acquire metastatic potential and cancer stemness, have been reported. However, cancer metastasis and treatment resistance remain unconquerable for many cancer patients, probably due to diverse evolutionary changes in cancer cells.

Clonal hematopoiesis (CH) driven by JAK2V617F is known to accelerate atherosclerosis through inflammasome activation and release of interleukin (IL)-1β and -18; yet, the specific contribution of IL-18 has remained unclear. In this study, we demonstrate that antibody inhibition of IL-18 in JAK2V617F CH mice increases plaque collagen but paradoxically promotes both early lesion growth and advanced necrotic core formation. Mechanistically, IL-18 blockade reverses absent in melanoma 2 inflammasome activation but shifts cell death toward apoptosis, and together with impaired efferocytosis, results in greater necrosis. These events are coordinated by reduced interferon gamma signaling, which enhances collagen deposition while decreasing expression of efferocytotic genes. Our findings challenge the prevailing notion that IL-18 inhibition stabilizes atherosclerotic plaques and provide new mechanistic insight into the interplay among inflammasome biology, adaptive immunity, and plaque stability.