DNA graphic

J. Michelle Kahlenberg, MD, PhD

Associate Professor

University of Michigan

Immunology

https://medicine.umich.edu/dept/immunology/j-michelle-kahlenberg-md-phd

Targeting Hippo signaling to downregulate IFN production in SLE

Lupus causes inflammation in many parts of the body, including the skin. Patients often have sensitivity to sunlight due to type I interferons (IFN-I), which are commonly overproduced in lupus patients and cause inflammation. Since interferons have many helpful jobs in the body, such as fighting infections, researchers are looking for ways to lower the high levels of interferons without completely blocking their ability to function in lupus patients.

Dr. Kahlenberg recently found that abnormal activity of Hippo proteins turns on the overproduction of interferons in SLE patients’ blood and skin. She will use the LRA Lupus Mechanisms and Targets Award to study whether blocking or interfering with the Hippo proteins activity will reduce IFN-I without completely turning off the interferons. Dr. Kahlenberg and her team will study how the Hippo proteins regulate interferons in the skin and blood, and test whether turning off the Hippo proteins lowers lupus disease activity by reducing IFN-I levels in mouse models of lupus.

What this study means for people with lupus

This research will provide new information on how interferons are regulated in lupus patients and determine whether Hippo proteins could be a new therapeutic target for the treatment of cutaneous lupus and SLE.

Overproduction of type I IFNs is a hallmark of systemic lupus erythematosus (SLE) patients, especially in the skin where 100% of skin lesions exhibit an elevated IFN score. Both keratinocytes (KCs) and myeloid cells contribute to type I IFN production in SLE patients. Importantly, there is a critical knowledge gap as to what regulates the propensity for increased interferon production in SLE. Addressing this gap will address a key research priority for the LRA and will lead to novel targets to precisely eliminate the pathogenic players in SLE/CLE, ideally without side effects or infectious risk, such as those generated by global IFN blockade. In our work to investigate pathologic regulators of SLE KCs, we have uncovered a role for functional dysregulation of the Hippo signaling pathway, a regulator of proliferation and apoptotic responses. Intriguingly, through work done primarily in the cancer field, the Hippo pathway has also been identified as a regulator of cGAS/STING activation, which is a critical activator of IFNs in response to nucleic acid sensing and ultraviolet (UV) light, an important trigger for SLE. Our preliminary data support that LATS1/2, critical kinases activated when the Hippo pathway is “on”, are chronically activated in SLE non-lesional skin and that inhibition of LATS1/2 can downregulate the STING-mediated overproduction of IFN-kappa, an important type I IFN in SLE skin. Thus, we hypothesize that chronic Hippo activation is a critical switch that permits hyperproduction of type I IFNs through amplification of cGAS-STING activation in SLE. This hypothesis will be addressed through the following aims: 1. Determine the activation status of STING regulators in SLE KCs, whether this can be modulated by inhibition of Hippo signaling, and how this affects KC activation of dendritic cells. 2. Determine the status of Hippo signaling and the extent to which it is modulates IFN production in SLE monocytes. 3. Investigate the potential for LATS1/2 inhibition to abrogate skin and kidney inflammation in murine models of lupus. Upon successful completion of these aims, we will characterize Hippo signaling as a rheostat for regulation of STING-driven type I IFN production in SLE keratinocytes and monocytes and will provide preclinical data on the utility of LATS1/2 inhibition to prevent or treat SLE.

Together, ManyOne Can make a difference!
Stay informed about events, research developments, and ways you can help. Sign up for updates