[Crohn's disease].

Sarcoidosis and the mTOR, Rac1, and Autophagy Triad.

Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids. An imprecise understanding of the immunologic changes underlying sarcoidosis has limited therapeutic progress. Here in this open-label trial (NCT03910543), 10 patients with cutaneous sarcoidosis are treated with tofacitinib, a Janus kinase inhibitor. The primary outcome is the change in the cutaneous sarcoidosis activity and morphology instrument (CSAMI) activity score after 6 months of treatment. Secondary outcomes included change in internal organ involvement, molecular parameters, and safety. All patients experience improvement in their skin with 6 patients showing a complete response. Improvement in internal organ involvement is also observed. CD4+ T cell-derived IFN-γ is identified as a central cytokine mediator of macrophage activation in sarcoidosis. Additional type 1 cytokines produced by distinct cell types, including IL-6, IL-12, IL-15 and GM-CSF, also associate with pathogenesis. Suppression of the activity of these cytokines, especially IFN-γ, correlates with clinical improvement. Our results thus show that tofacitinib treatment is associated with improved sarcoidosis symptoms, and predominantly acts by inhibiting type 1 immunity. 

/pdf/inhibition-of-type-1-immunity-with-tofacitinib-is-associated-39nh91e5.pdf

Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis

Metabolic reprogramming is rapidly gaining appreciation in the etiology of immune cell dysfunction in a variety of diseases. Tuberculosis, schistosomiasis, and sarcoidosis represent an important class of diseases characterized by the formation of granulomas, where macrophages are causatively implicated in disease pathogenesis. Recent studies support the incidence of macrophage metabolic reprogramming in granulomas of both infectious and non-infectious origin. These publications identify the mechanistic target of rapamycin (mTOR), as well as the major regulators of lipid metabolism and cellular energy balance, peroxisome proliferator receptor gamma (PPAR-γ) and adenosine monophosphate-activated protein kinase (AMPK), respectively, as key players in the pathological progression of granulomas. In this review, we present a comprehensive breakdown of emerging research on the link between macrophage cell metabolism and granulomas of different etiology, and how parallels can be drawn between different forms of granulomatous disease. In particular, we discuss the role of PPAR-γ signaling and lipid metabolism, which are currently the best-represented metabolic pathways in this context, and we highlight dysregulated lipid metabolism as a common denominator in granulomatous disease progression. This review therefore aims to highlight metabolic mechanisms of granuloma immune cell fate and open up research questions for the identification of potential therapeutic targets in the future.

/pdf/metabolic-programming-of-macrophages-implications-in-the-1ktrbwboys.pdf

Metabolic Programming of Macrophages: Implications in the Pathogenesis of Granulomatous Disease

Monocytes and macrophages are innate immune cells with diverse functions ranging from phagocytosis of microorganisms to forming a bridge with the adaptive immune system. A lesser-known attribute of macrophages is their ability to fuse with each other to form multinucleated giant cells. Based on their morphology and functional characteristics, there are in general three types of multinucleated giant cells including osteoclasts, foreign body giant cells and Langhans giant cells. Osteoclasts are bone resorbing cells and under physiological conditions they participate in bone remodeling. However, under pathological conditions such as rheumatoid arthritis and osteoporosis, osteoclasts are responsible for bone destruction and bone loss. Foreign body giant cells and Langhans giant cells appear only under pathological conditions. While foreign body giant cells are found in immune reactions against foreign material, including implants, Langhans giant cells are associated with granulomas in infectious and non-infectious diseases. The functionality and fusion mechanism of osteoclasts are being elucidated, however, our knowledge on the functions of foreign body giant cells and Langhans giant cells is limited. In this review, we describe and compare the phenotypic aspects, biological and functional activities of the three types of multinucleated giant cells. Furthermore, we provide an overview of the multinucleation process and highlight key molecules in the different phases of macrophage fusion.

https://www.frontiersin.org/articles/10.3389/fcell.2022.873226/pdf

Multinucleated Giant Cells: Current Insights in Phenotype, Biological Activities, and Mechanism of Formation

The mechanisms underlying abnormal granuloma formation in patients with sarcoidosis are complex and remain poorly understood. A novel in vitro human granuloma model was used to determine the molecu...

/pdf/il-13-regulated-macrophage-polarization-during-granuloma-2rxwwy9516.pdf

IL-13-regulated Macrophage Polarization during Granuloma Formation in an In Vitro Human Sarcoidosis Model.

Introduction: Sarcoidosis is a chronic granulomatous inflammatory disease that commonly causes lung disease, but can affect other vital organs and tissues. The cause of sarcoidosis is unkno...

Potential immunotherapies for sarcoidosis.

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IL-13-regulated Macrophage Polarization during Granuloma Formation in an In Vitro Human Sarcoidosis Model.

Potential immunotherapies for sarcoidosis.