Immune Response to Infection Independent of the Inflammatory Pathway

Recent findings revealed that the immune system's response to infection involves the release of cytokines that trigger two parallel signaling pathways, one that activates immune cells to deal with invading microorganisms and another that causes inflammation and damage to vascular and connective tissues.


Up to now most immunologists have believed that macrophages and other cells responded to infection by releasing cytokines, such as interleukin-1beta (IL-1beta), which in turn activated a well-described, myeloid-differentiation factor 88 (MYD88)-mediated, nuclear factor-kappaB (NF-kappaB)-dependent transcriptional pathway that resulted in inflammatory-cell activation and recruitment. However, the cytokines that are vital to a successful immune defense also have disruptive effects on endothelial cell–cell interactions and can trigger degradation of barrier functions and dissociation of tissue architecture. Furthermore, it was felt that treatment to prevent inflammation could compromise the immune system's attempts to deal with the infection.


Investigators at the University of Utah (Salt Lake City, USA) have found evidence that suggests that the immune system's response to infection is more complex. They reported in the November 11, 2012, online edition of the journal Nature that IL-1beta actually initiated two independent signaling pathways. In addition to the NF-kappaB -mediated pathway that fights infection, there was a second pathway that was responsible for cellular damage and inflammation.

The second pathway depended on signaling through the small GTPase ADP-ribosylation factor 6 (ARF6) and its activator ARF nucleotide binding site opener (ARNO; also known as CYTH2). ARNO bound directly to the adaptor protein MYD88, and MYD88–ARNO–ARF6 functioned as an IL-1beta-initiated signaling pathway distinct from that mediated by NF-kappaB.

The existence of the second pathway was confirmed by results that showed that treatment with SecinH3, an inhibitor of ARTF guanine nucleotide-exchange factors such as ARNO, enhanced vascular stability and significantly improved outcomes in animal models of inflammatory arthritis and acute inflammation.

“We can selectively block inflammation without making the patient immunosuppressed,” said senior author Dr. Dean Y. Li, professor of medicine at the University of Utah. “This rewrites the strategy for today’s medicines. We focused the work on arthritis given this is a proven market for drugs that reduce damage from inflammation and fibrosis, but we suspect that many other diseases ranging from fibrosis following heart attacks to inflammatory bowel disease may benefit from such an approach.”

“This can change the way medication is made,” said Dr. Li. “If we can find a way to replace our most powerful drugs for arthritis, we might be able to develop another way to treat inflammation in other diseases that we have been unable to touch because of the danger of suppressing people’s immune systems.”

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