Role of fat-associated lymphoid clusters

Role of fat-associated lymphoid clusters

Some of our fat deposits, such as the omentum (the main abdominal fat) and the pericardium (around the heart) are rich in immune clusters containing IgM producing B cells important for early protection during infection. In addition, these immune clusters recruit large amounts of inflammatory cells during episodes of inflammation triggered by events such as peritonitis, pericarditis and myocardial infarction. Our lab aims to elucidate the function of these clusters and the mechanisms underlying their role in infection, inflammation and obesity.

Role of the pericardium during airway infections:

Fat-associated lymphoid clusters (FALC) are inducible structures that support rapid innate-like B-cell immune responses in the serous cavities. Little is known about the physiological cues that activate FALCs in the pleural cavity and more generally the mechanisms controlling B-cell activation in FALCs. Using separate models of pleural nematode infection with Litomosoides sigmodontis and Altenaria alternata induced acute lung inflammation, that inflammation of the pleural cavity rapidly activates mediastinal and pericardial FALCs. IL-33 produced by FALC stroma is crucial for pleural B1-cell activation and local IgM secretion. However, B1 cells are not the direct target of IL-33, which instead requires IL-5 for activation. Moreover, lung inflammation leads to increased IL-5 production by type 2 cytokine-producing innate lymphoid cells (ILC2) in the FALC. Our work reveal a link between inflammation, IL-33 release by FALC stromal cells, ILC2 activation and pleural B-cell activation in FALCs, resulting in local and antigen-specific IgM production.

Current work is investigating the importance of IgM produced by the pericardium for protection against airway viral infections such as influenza. In addition we are studying how viral infections contribute to changes in the properties of the pericardium that could link higher susceptibility to myocardial infarction during episodes of acute airway infections.

Fat-associated lymphoid clusters control local IgM secretion during pleural infection and lung inflammation. Jackson-Jones LH, Duncan SM, Magalhaes MS, Campbell SM, Maizels RM, McSorley HJ, Allen JE, Bénézech C. Nat Commun. 2016 Sep 1;7:12651. doi: 10.1038/ncomms12651.

Control of innate-like B cell location for compartmentalised IgM production. Jackson-Jones LH, Bénézech C. Curr Opin Immunol. 2018 Feb;50:9-13. doi: 10.1016/j.coi.2017.10.006. Epub 2017 Nov 5. Review.

Role of the omentum in peritoneal inflammation:

Obesity has become a major health issue in most industrialised countries. It predisposes to cardiovascular disease and is associated with premature mortality. Chronic inflammation in adipose tissue is important in obesity, but use of anti-inflammatory therapies has had very modest or no efficacy in restoring metabolic health. Recent studies showed that stimulations of certain populations of immune cells in adipose tissue could improve inflammation, induce weight loss and ameliorate type 2 diabetes. But the precise mechanisms involved remain unknown. One fat depot, the omentum, is particularly rich in immune clusters where inflammatory cells are concentrating during infection and peritonitis (inflammation of the peritoneal cavity). In this project, we want to understand the role of the omentum in the regulation of inflammation and the development of obesity. In particular we wish to elucidate whether this organ is responsible for the beneficial effect of immune-intervention in obesity.  We use models of peritonitis to study the role of the omentum in inflammation to enhance our knowledge concerning the mechanisms underlying inflammation and the defense of the peritoneal cavity against infections and open new roads for the development of therapeutics tools in the treatment of inflammation in obesity. We are  examining the role of the omentum in the development of obesity and its treatment by immune-intervention. This work will pave the way to future translational studies looking at the omentum in humans and the therapeutic benefit of their targeting in inflammatory settings (such as appendicitis and pancreatitis) and in obesity.

Inflammation-induced formation of fat-associated lymphoid clusters. Bénézech C, Luu NT, Walker JA, Kruglov AA, Loo Y, Nakamura K, Zhang Y, Nayar S, Jones LH, Flores-Langarica A, McIntosh A, Marshall J, Barone F, Besra G, Miles K, Allen JE, Gray M, Kollias G, Cunningham AF, Withers DR, Toellner KM, Jones ND, Veldhoen M, Nedospasov SA, McKenzie ANJ, Caamaño JH. Nat Immunol. 2015 Aug;16(8):819-828. doi: 10.1038/ni.3215. Epub 2015 Jun 29

 

Principal Investigator: Cecile Benezech

Lab members: Marlene Magalhaes, Peter Smith

Collaborators: Lucy Jackson-Jones (University of Lancaster), Damian Mole (CIR), Judith Allen (University of Manchester), Gillian Gray (CVS), Katie Mylonas (CIR), Marc Dweck (CVS)

 

This work is founded by the MRC, the Sylvia Waddilove foundation, Tenovus Scotland and ISSF2.