Monday, December 19, 2022

Interleukin-37 both suppresses and stimulates inflammation - A surprise discovery

When scientists err, human lives can be in danger or important medical treatment is delayed! Perhaps, this study is very narrowly focused, but it is an example.

"... Scientists ... have made an important breakthrough in understanding how inflammation is regulated. They have just discovered that a key immune alarm protein previously believed to calm down the immune response actually does the opposite. Their work has numerous potential impacts, especially in the context of understanding and responding to autoimmune disorders and inflammation. ...
"Interleukins play key roles in regulating our immune systems in response to bacterial and fungal infections. However, Interleukin-37 has long remained an enigma, as it isn't found in mammals such as mice. ..." ...
"This pro-inflammatory impact was highly unexpected. Our work shows that the protein binds to an interleukin receptor in the skin that is known to play a key role in driving psoriasis. ... this brings the total number of immune alarm molecules that signal via this particular interleukin receptor to four.
"Why there are so many interleukins that bind to the same receptor is a mystery, but if we were to speculate it may be because this receptor serves a very important sentinel function in our skin, and that one alarm protein may simply not be enough to respond to the many different infectious agents that our skin encounters.  ..." ..."

"IL-37, pro-inflammatory after all
Interleukin-37 (IL-37), like other members of the extended IL-1 family, contains an N-terminal pro-domain that requires proteolytic cleavage for its activity. While the full activity of IL-37 remains unknown, prior work has demonstrated that IL-37 cleaved by caspase-1 can suppress inflammatory cytokine production. Sullivan et al. show that IL-37 can also be cleaved by neutrophil elastase and cathepsin S, generating an active form that stimulates robust pro-inflammatory cytokine production in human keratinocytes. IL-37 truncated at the cathepsin S cleavage site induced a similar pro-inflammatory response in the murine peritoneal cavity and required the IL-36 receptor, identifying IL-37 as a putative IL-36R ligand. Together, these results show that, when cleaved at specific sites, IL-37 can also stimulate pro-inflammatory responses in line with other IL-1 family member proteins."

From the abstract:
"Interleukin-1 (IL-1) family cytokines are key barrier cytokines that are typically expressed as inactive, or partially active, precursors that require proteolysis within their amino termini for activation. IL-37 is an enigmatic member of the IL-1 family that has been proposed to be activated by caspase-1 and to exert anti-inflammatory activity through engagement of the IL-18R and SIGIRR. However, here we show that the longest IL-37 isoform, IL-37b, exhibits robust proinflammatory activity upon amino-terminal proteolysis by neutrophil elastase or cathepsin S. In sharp contrast, caspase-1 failed to process or activate IL-37 at concentrations that robustly activated its canonical substrate, IL-1β. IL-37 and IL-36 exhibit high structural homology, and, consistent with this, a K53-truncated form of IL-37, mimicking the cathepsin S–processed form of this cytokine, was found to exert its proinflammatory effects via IL-36 receptor engagement and produced an inflammatory signature practically identical to IL-36. Administration of K53-truncated IL-37b intraperitoneally into wild-type mice also elicited an inflammatory response that was attenuated in IL-36R−/− animals. These data demonstrate that, in common with other IL-1 family members, mature IL-37 can also elicit proinflammatory effects upon processing by specific proteases."

Immune surprise: Recently evolved alarm molecule drives inflammation


Cells expressing inflammatory cytokines, stained green


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