PU.1 and IRF8 Modulate Activation of NLRP3 Inflammasome via Regulating Its Expression in Human Macrophages

Feng

Journal of Healthcare Engineering

et al. 2022

Cryptococcus is one of the most pathogenic invasive fungi, and its interaction with the host’s natural immunity, especially the role of the inflammasome family, has not been fully elucidated. As an important member of the inflammasome family, NOD-like receptor (NLR) family caspase recruitment domain (CARD) containing 4 (NLRC4) has been proven to protect lungs from damage from a variety of pathogens. In this study, we investigated the protective effect and mechanism of NLRC4 on cryptococcal pulmonary infection using NLRC4-/-mice in vivo and NLRC4-/-macrophages in vitro models stimulated by cryptococcal cells. We apply small animal fluorescence imaging to detect the fungal burden in the lungs and living body micro-CT scans of mice and in vitro tissue micro-CT scans to compare differences in infection foci nodules and histopathological lesions, and the activation of caspase-1 and downstream cytokines were detected by Western bolt and ELISA, etc. The results demonstrated that cryptococcal infection can activate the Nod-like receptors of caspase-1 activation and NLRC4 inflammasomes in macrophages and dendritic cells and affect downstream IL-1β and IL-18 release. After cryptococcal infection, the survival rate, lung fungal burden, and histopathological damage of NLRC4-/- mice were significantly impaired. NLRC4-/- macrophages showed a lower release of inflammatory factors, reactive oxygen species (ROS), and lactate dehydrogenase (LDH). Collectively, our results demonstrated that the activation of caspase-1 and downstream cytokines mediated by NLRC4 inflammasome in immune cells during Cryptococcus infection can enhance pyroptosis of macrophages, affect the phagocytic ability of macrophages, and inhibit the intracellular parasitism of cryptococcus, eventually reducing the burden of fungi.

Section: Introductionmentioning

confidence: 99%

The Inflammasome NLRC4 Protects against Cryptococcus gattii by Inducing the Classic Caspase-1 to Activate the Pyroptosis Signal

Feng

Journal of Healthcare Engineering

et al. 2022

“…THP-1 cells were used to study the secretion of the inflammasome by inflammatory cells in acne lesions. Since it is well documented that cultured THP-1 has the molecular constitution required for inflammasome assembly [ 29 ], we sought to confirm whether P. acnes stimulates the secretion of IL-1β in vitro. After cells were treated with active P. acnes , IL-1β expression in the cytoplasm was up-regulated at the transcription level (Fig.…”

Section: Resultsmentioning

confidence: 99%

Adipose-derived stem cells attenuate acne-related inflammation via suppression of NLRP3 inflammasome

Luo

Chen

et al. 2022

Stem Cell Res Ther

Background Acne is a chronic facial disease caused by Propionibacterium acnes, which proliferates within sebum-blocked skin follicles and increases inflammatory cytokine production. Several therapeutic drugs and products have been proposed to treat acne, yet no single treatment that ensures long-term treatment efficacy for all patients is available. Here, we explored the use of facial autologous fat transplant of adipose-derived stem cells (ADSCs) to dramatically reduce acne lesions. Methods THP-1 cells were treated with active P. acnes for 24 h at different multiplicities of infection, and alterations in inflammatory factors were detected. To study the effect of THP-1 on inflammasome-related proteins, we first co-cultured ADSCs with THP-1 cells treated with P. acnes and evaluated the levels of these proteins in the supernatant. Further, an acne mouse model injected with ADSCs was used to assess inflammatory changes. Results Propionibacterium acnes-mediated stimulation of THP-1 cells had a direct correlation with the expression of active caspase-1 and interleukin (IL)-1β in an infection-dependent manner. ADSCs significantly reduced the production of IL-1β induced by P. acnes stimulation through the reactive oxygen species (ROS)/Nod-like receptor family pyrin domain-containing 3 (NLRP3)/caspase-1 pathway. The results showed that ADSCs inhibit the skin inflammation induced by P. acnes by blocking the NLRP3 inflammasome via reducing the secretion of IL-1β in vivo. Conclusions Our findings suggest that ADSCs can alter IL-1β secretion by restricting the production of mitochondria ROS, thereby inhibiting the NLRP3/caspase-1 pathway in P. acnes-induced inflammatory responses. This study indicates that anti‐acne therapy can potentially be developed by targeting the NLRP3 inflammasome.

“…PU.1 is also involved in macrophage-involved inflammation, studies have shown, PU. 1 activates macrophages and increases the inflammatory response by regulating NLRP3 inflammasome [ 41 ]. Interestingly, PU.1 may serve as an important target for vitamin D3 to alleviate atopic dermatitis, a severe inflammatory skin disease [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Macrophages mediate psoriasis via Mincle-dependent mechanism in mice

et al. 2023

Psoriasis is currently considered to be an immune and inflammatory disease characterized by massive immune cells infiltration including macrophages. It has been reported that macrophage-inducible C-type lectin (Mincle) is essential to maintain the pro-inflammatory phenotype of M1 macrophages, however, its role and mechanisms in psoriasis remain largely unknown. A model of psoriasis was induced in mice by a daily topical application of imiquimod for 7 days. Role and mechanisms of Mincle in macrophage-mediated psoriasis were investigated in clodronate liposomes induced macrophage depletion mice followed by adoptively transferring with Mincle-expressing or -knockout (KO) macrophages, and in macrophage specific Mincle knockout mice (Mincleloxp/loxp/Lyz2-cre+/+). Finally, a Mincle neutralizing antibody was employed to the psoriasis mice to reveal the therapeutic potential for psoriasis by targeting Mincle. Mincle was highly expressed by M1 macrophages in the skin lesions of patients and mice with psoriasis. Clodronate liposomes-induced macrophage depletion inhibited psoriasis in mice, which was restored by adoptive transfer with Mincle-expressing macrophages but not by Mincle-KO macrophages. This was further confirmed in macrophage-specific Mincle-KO mice. Mechanistically, macrophages mediated psoriasis via the Mincle-Syk-NF-κB pathway as blocking macrophage Mincle inhibited Syk/NF-κB-driven skin lesions and epidermal injury in vivo and in vitro. We also found that LPS induced Mincle expression by M1 macrophages via the PU.1-dependent mechanism. Most importantly, we revealed that targeting Mincle with a neutralizing antibody significantly improved psoriasis in mice. In summary, our findings demonstrated that macrophages mediate psoriasis in mice via the Mincle-dependent mechanism, targeting Mincle may represent as a novel therapy for psoriasis.