( urrent fever skin rash and arthritis. ...)Microbes start immune response by sneaking inside cells

Cryopyrin triggers a key enzyme involved in the body’s inflammatory response, capsase-1, which in turn causes production of IL-1beta, a powerful molecule which signals the immune system to attack pathogens and induces fever to help the body fend off infection. IL-1beta plays an important role, too, in excessive immune system activity in inflammatory diseases.

The researchers report in the new paper how cryopyrin is activated to start the process. In experiments that exposed mouse immune cells called macrophages to bacteria, Thirumala-Devi Kanneganti, Ph.D., a U-M research investigator in pathology, and Mohamed Lamkanfi, Ph. D, a U-M research fellow, the study’s co-first authors, find that cryopyrin’s call to action inside the cells occurs without requiring a well-known set of cell-surface receptors called Toll-like receptors or TLRs. ”We prove that these TLRs are not required to activate cryopyrin. That is a major step,?says Nunez.

Instead, bacteria were able to enter the cells through a pore in the cell membrane, and stimulate the cryopyrin-initiated immune response without activating TLRs. The researchers discovered that a protein called pannexin-1 creates the pore, like a devious undersea diver drilling a hole in a ship hull.

The team’s work joins a growing body of research revealing the importance of recently discovered receptors such as cryopyrin inside cells, known collectively as NOD-like receptors. Knowledge about NOD-like receptors is moving forward rapidly and will contribute to a fuller understanding of the human immune system, say the U-M researchers.