Linking il-10 signaling with lipid metabolic programs in macrophages: dysregulated ceramide homeostasis drives colitis

In a recent study published in _Nature_, York and coworkers identified the immunometabolic regulation of mono-unsaturated fatty acid (MUFA) pools and the subsequent increase in sphingolipid

biosynthesis in TLR2-activated macrophages as an important link between impaired IL-10 signaling and the development of intestinal inflammation.1 Thus, targeted interference with the newly

identified IL-10/MUFA/sphingolipid axis appears as a promising strategy to restore immunometabolic homeostasis in the intestine of patients with inflammatory bowel diseases (IBD). The

critical dependence of gut health on the anti-inflammatory cytokine IL-10 is well established.2 To mention some key evidence, knockout (KO) mice lacking IL-10 or one of the IL-10 receptor

subunits develop spontaneous colitis, while mutations within the coding region of the human IL-10 or IL-10 receptor genes account for a relevant percentage of patients diagnosed with very

early-onset IBD. Although IL-10 can be sensed by various immune cells, a macrophage-restricted loss of the IL-10RA receptor subunit was sufficient to induce spontaneous colitis, implicating

mucosal macrophages as central mediators of anti-inflammatory IL-10 signaling.2 Despite the well-described colitis-promoting consequence of in vivo IL-10 blockade/neutralization, the

intracellular cascade linking IL-10 receptor ligation to the regulation of inflammatory macrophage function remains incompletely understood. Interestingly, a previous study suggested that

the anti-inflammatory function of IL-10 in macrophages involves its ability to block activation-induced metabolic reprogramming, thus describing its cellular effects as an interplay between

immunological signaling and metabolic regulation.3 From a translational perspective, there is a growing awareness of the relevance of metabolic processes for immune cell function in the

context of IBD. This awareness arises in particular from the clinical need to offer optimized treatment strategies to more than 30% of IBD patients who do not show a satisfying response to

the currently available therapeutic regimens. New targets that allow modulation of the metabolic response of immune cells to inflammatory triggers, rather than exclusively blocking classical

immune mediators upstream or downstream of cytokine receptors, may be particularly beneficial for those IBD patients who do not respond to biological agents such as anti-TNF therapy,

vedolizumab, p19/p40 blockers and JAK inhibitors. Since the lipid pool in macrophages is known to be altered during TLR-mediated activation, York et al.1 first focused on whether this

reprogramming of lipid metabolism depends on IL-10, whose secretion by macrophages is also induced by TLR ligation. Indeed, the lipid metabolomic data indicated that TLR2-induced IL-10

signaling significantly affects sphingolipid metabolism of macrophages. Based on direct infusion mass spectrometry, TLR2-activated IL-10-deficient macrophages could be characterized by

increased levels of ceramides and hexosyl ceramides compared to IL-10-positive control macrophages, whereas all unsaturated and some saturated sphingomyelins were decreased in the absence of

IL-10. The accumulation of ceramides in TLR2-activated IL-10 KO macrophages appeared to be driven by increased de novo ceramide synthesis. Accordingly, genetic deletion of ceramide synthase

Cers2, an enzyme that controls very long chain (VLC) ceramide synthesis, prevented the induction of inflammatory genes in in vitro activated macrophages by IL-10R blockade and, under in

vivo conditions, IL-10 receptor/Cers2 double knockout bone marrow chimeric mice showed milder signs of intestinal inflammation than cohoused IL-10 receptor knockout chimeric mice. The next

step was to elucidate the cascade underlying the regulation of ceramide biosynthesis and the accumulation of VLC ceramides in IL-10 KO macrophages. Somewhat unexpectedly, the expression

levels of all genes directly involved in sphingolipid metabolism turned out to be comparable between IL-10 KO and control macrophages. However, IL-10 deficiency in macrophages caused a

significant downregulation of the enzyme stearoyl-CoA desaturase 2 (SCD2), which catalyzes the formation of MUFAs. These findings led to the hypothesis that MUFA synthesis links inflammation

and VLC ceramide synthesis in IL-10 KO macrophages. Indeed, stable-isotope tracer analysis indicated that the reduced SCD2 expression in TLR2-stimulated IL-10 KO macrophages was associated

with reduced MUFA synthesis, whereas the inflammatory gene expression profile of IL-10 KO macrophages and their increased VLC ceramide biosynthesis could be attenuated by exogenous MUFA

supplementation. Furthermore, SCD2-deficient macrophages phenocopied IL-10 KO macrophages in terms of VLC ceramide accumulation and increased inflammatory gene expression. Taken together,

York et al. were able to identify the insufficient capacity of IL-10-deficient macrophages to upregulate MUFA synthesis as the underlying cause of their pathologically enhanced inflammatory

activity (Fig. 1). But how does the IL-10-controlled availability of VLC ceramides affect the regulation of inflammatory genes? York et al.1 interestingly demonstrated that the NF-kappaB

family transcription factor REL is required for the ability of VLC ceramides to induce inflammatory gene expression in TLR2-activated macrophages and, accordingly, for the full development

of intestinal inflammation in IL-10-deficient mice. Interestingly, in vitro analyses of activated IL-10/c-Rel double knockout macrophages implicated that the ceramide-induced activation of

REL predominantly supports the prolonged maintenance of inflammatory gene expression rather than enhancing its early initiation. Regarding the therapeutic targetability of IL-10 signaling,

previous data from experimental mouse models suggested that direct administration of recombinant IL-10 may ameliorate colitis,2 but clinical IBD trials have been disappointing overall. The

new insights into the immunometabolic cascade that is initiated when macrophages are activated in the absence of IL-10 signaling may pave the way for more clinically successful strategies to

elicit IL-10-triggered anti-inflammatory effects, which may even be beneficial for IBD patients with IL-10 receptor dysfunction. Nutritional MUFA supplementation or targeted blockade of the

VLC ceramide synthesis via inhibition of Cers2 appear, at least on the first view, as two attractive strategies in this context (Fig. 1). However, assuming that both these approaches cannot

be implemented in a macrophage-restricted way, their expected impact on other cells involved in the maintenance of intestinal homeostasis must be considered. One potential limitation of the

study is the lack of validation in other IL-10 receptor-expressing intestinal immune cells, including those of humans. Cers2 represents a tumor metastasis suppressor gene,4 and defined

MUFAs have been associated with enhanced T effector cell function5 underlining potential risk factors when targeting this pathway. Thus, the validation of the findings on the IL-10/MUFA/VLC

ceramide/REL axis in other IL-10 receptor-expressing intestinal immune cells, in addition to macrophages, is essential. Moreover, the validation of this axis in human immune cells in the

inflamed intestine of IBD patients is of paramount importance. The more complete the molecular consequences of insufficient IL-10 signaling in innate and adaptive immune cells and in the

intestinal epithelium can be deciphered, the better the chances are to fully exploit the high translational potential of this study. In terms of personalized medicine, rationally designed

biomarker strategies based on the intestinal expression profile of genes/proteins that regulate MUFA synthesis and/or REL activation could reliably identify individual IBD patients with

relevant impaired IL-10 signaling who could best benefit from targeted local corrections of MUFA/VLC ceramide homeostasis. REFERENCES * York, A. G. et al. IL-10 constrains sphingolipid

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ACKNOWLEDGEMENTS The work was supported by the following grants from the DFG; German Research Foundation: TRR241 (project number 375876048) and AT 122/2-1 (project number 511510453). In

addition, this work was supported by the Interdisciplinary Center for Clinical Research Erlangen: IZKF D37. FUNDING Open Access funding enabled and organized by Projekt DEAL. AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * Department of Medicine 1, University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany Imke Atreya & Markus

F. Neurath * Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany Imke Atreya & Markus F. Neurath Authors * Imke Atreya View author publications You can also search for this author

inPubMed Google Scholar * Markus F. Neurath View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS M.F.N. and I.A. drafted the manuscript and the

figure. All authors critically revised the manuscript for important intellectual content. All authors have read and approved the article. CORRESPONDING AUTHOR Correspondence to Markus F.

Neurath. ETHICS DECLARATIONS COMPETING INTERESTS M.F.N. has served as an advisor for Pentax, Giuliani, PPM, MSD, Abbvie, Janssen, Takeda and Boehringer. IA discloses no conflicts. RIGHTS AND

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Neurath, M.F. Linking IL-10 signaling with lipid metabolic programs in macrophages: dysregulated ceramide homeostasis drives colitis. _Sig Transduct Target Ther_ 9, 156 (2024).

https://doi.org/10.1038/s41392-024-01864-7 Download citation * Received: 15 March 2024 * Revised: 26 April 2024 * Accepted: 06 May 2024 * Published: 08 June 2024 * DOI:

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