When UV light hits the skin it can damage important cellular molecules, sparking inflammation as a common consequence. However, it is unclear how this exactly happens. Researchers at the University of Bonn report they have uncovered a pathway that can trigger the inflammatory responses that are a result of UV or skin damage.
The findings, “P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection,” are published in the Journal of Experimental Medicine.
“Inflammasomes integrate cytosolic evidence of infection or damage to mount inflammatory responses,” wrote the researchers. “The inflammasome sensor NLRP1 is expressed in human keratinocytes and coordinates inflammation in the skin. We found that diverse stress signals induce human NLRP1 inflammasome assembly by activating MAP kinase p38: While the ribotoxic stress response to UV and microbial molecules exclusively activates p38 through MAP3K ZAKα, infection with arthropod-borne alphaviruses, including Semliki Forest and chikungunya virus, activates p38 through ZAKα and potentially other MAP3K. We demonstrate that p38 directly phosphorylates NLRP1 and that serine 107 in the linker region is critical for activation.”
“In our study, we took a closer look at the processes involved,” explained Florian Schmidt, PhD, who leads a research group at the Institute of Innate Immunity at the University Hospital Bonn.
“We have now been able to show that a known cellular stress signaling pathway can trigger these inflammatory responses,” added Schmidt.
Their findings demonstrate that p38 molecularly modifies NLRP1, a critical switch for inflammation in the skin.
“We were able to show that mosquito-borne viruses can activate NLRP1 through p38 as well,” emphasized Lea-Marie Jenster, a PhD student in the Schmidt lab and the lead author of this study. “These include, for instance, chikungunya virus, which is a major problem in parts of Africa and Asia and could also reach Germany in the wake of climate change.” Viruses probably even trigger the activation of p38 via several different pathways.
“P38 is a molecular information hub in the skin, in which various warning signals converge—similar to the fire department’s control center,” Schmidt explained. “However, not every incoming call for help immediately triggers the assembly of inflammasomes—this only happens when the number and intensity of alerts exceed a certain threshold.”
The researchers believe p38 may open up a new possibility to specifically suppress such exuberant immune reactions in the skin.