The Caenorhabditis elegans Germ Line Regulates Distinct Signaling Pathways to Control Lifespan and Innate Immunity

Scott Alper,Matthew K Mcelwee,Javier Apfeld,Brad Lackford,Jonathan H Freedman,David A Schwartz

doi:10.1074/jbc.m109.057323

Abstract

The relationship between the mechanisms that control an organism's lifespan and its ability to respond to environmental challenges are poorly understood. In Caenorhabditis elegans, an insulin-like signaling pathway modulates lifespan and the innate immune response to bacterial pathogens via a common mechanism involving transcriptional regulation by the DAF-16/FOXO transcription factor. The C. elegans germ line also modulates lifespan in a daf-16-dependent manner. Here, we show that the germ line controls the innate immune response of C. elegans somatic cells to two different Gram-negative bacteria. In contrast to the insulin-like signaling pathway, the germ line acts via distinct signaling pathways to control lifespan and innate immunity. Under standard nematode culture conditions, the germ line regulates innate immunity in parallel to a known p38 MAPK signaling pathway, via a daf-16-independent pathway. Our findings indicate that a complex regulatory network integrates inputs from insulin-like signaling, p38 MAPK signaling, and germ line stem cells to control innate immunity in C. elegans. We also confirm that innate immunity and lifespan in C. elegans are distinct processes, as nonoverlapping regulatory networks control survival in the presence of pathogenic and nonpathogenic bacteria. Finally, we demonstrate that the p38 MAPK pathway in C. elegans is activated to a similar extent by both pathogenic and nonpathogenic bacteria, suggesting that both can induce the nematode innate immune response.

Highlights

From the ‡Integrated Department of Immunology and ‡‡Department of Medicine, National Jewish Health, Denver, Colorado 80206, the §Laboratory of Molecular Toxicology and **Laboratory of Molecular Carcinogenesis, NIEHS, National Institutes of Health, Durham, North Carolina 27709, the ʈHarvard Medical School Department of Systems Biology, Boston, Massachusetts, 02115, and the ¶Nicholas School of the Environment, Duke University, Durham, North Carolina 27707
Our findings indicate that a complex regulatory network integrates inputs from insulin-like signaling, p38 MAPK signaling, and germ line stem cells to control innate immunity in C. elegans
Our findings indicate that the germ line acts in parallel to a p38 MAPK2 pathway to induce changes in innate immunity, suggesting that there are additional regulatory components of C. elegans host defense

Summary

The Caenorhabditis elegans Germ Line Regulates

In Caenorhabditis elegans, an insulin-like signaling pathway modulates lifespan and the innate immune response to bacterial pathogens via a common mechanism involving transcriptional regulation by the DAF-16/ FOXO transcription factor. We demonstrate that the p38 MAPK pathway in C. elegans is activated to a similar extent by both pathogenic and nonpathogenic bacteria, suggesting that both can induce the nematode innate immune response. In Caenorhabditis elegans, inhibition of either daf-2 insulin/ IGF-1-like signaling or germ line proliferation increases nematode lifespan [1,2,3,4], increases resistance to environmental stress [1, 5,6,7,8,9,10,11], and increases nematode survival in the presence of pathogen [12,13,14].

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION