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Table 2 Tissue Scale Rules

From: The innate immune response to ischemic injury: a multiscale modeling perspective

Rule

Literature support

Relevant references

CCL2 and ROS < − from intracellular model

1

Injury (2)* = 0 if M2 = 1 and previous injury = 1

M2 macrophages will resolve tissue damage due to injury.

[1, 82,83,84]

2

DAMPs (3) = 0 if Injury = 0 AND ROS = 0 regardless of M2

DAMPs are generally not accessible without tissue damage.

[85, 86]

3

DAMPs =0 if (Injury = 1 XOR** ROS = 1) and M2 = 1

M2 macrophages can completely resolve damage due to either injury or ROS.

[85,86,87,88,89,90,91,92]

4

DAMPs =1 if (Injury = 1 XOR** ROS = 1) and M2 = 0 unless previous DAMPs = 2

Lack of M2 macrophages leads to increased tissue damage in response to injury or ROS unless overwhelming damage.

[85,86,87,88,89,90,91,92]

5

DAMPs =1 if (Injury = 1 AND ROS = 1) and M2 = 1

Extensive damage resulting from both injury and ROS in the presence of M2 is not completely resolved.

[85,86,87,88,89,90,91,92]

6

DAMPs =2 if (Injury = 1 AND ROS = 1) and M2 = 0

Excess injury triggers an overwhelming immune response that destroys the tissue in the absence of M2 macrophages.

[85,86,87,88,89,90,91,92]

7

M1 (3) = 0 if (CCL2 = 0)

Pro-inflammatory cytokines (exemplified by CCL2) are required to recruit M1 monocytes/macrophages.

[1, 5, 67, 82,83,84, 93]

8

M1 = 1 if CCL2 = 1

Macrophage recruitment is initiated in response to cytokines.

[1, 5, 67, 82,83,84, 93]

9

M1 = 2 CCL2 = 2

increased cytokine levels result in more M1 macrophages.

[1, 5, 67, 82,83,84, 93]

10

M2 (2) = 1 if M1 = 1

M1 macrophages differentiate into M2.

[1, 5, 67, 82,83,84, 93]

11

M2 = 0 otherwise

M1s must exist to differentiate into M2s; and overwhelming M1 infiltration overcomes M2.

[1, 5, 67, 82,83,84, 93]

Intracellular scale rules

DAMPs and M2 < − from tissue model

12

CD13 (2)* = 1 if DAMPs = 1 or 2

CD13 is phosphorylated upon ligand binding to TLR4

[49, 71, 94]

13

CD13 = 0 otherwise

CD13 is not activated without inflammation

[49]

14

TRIF (3) = 0 if DAMPs = 0 regardless of CD13

There is no response without tissue damage.

[25, 49, 95]

15

TRIF = 1 if (DAMPs = 1) and (CD13 = 1)

Ligation and endocytosis of TLR4 triggers TRIF activation.

[25, 49, 95]

16

TRIF = 2 if (DAMPs = 1) and (CD13 = 0)

TRIF is hyper-activated in the absence of CD13

[25, 49, 95]

17

TRIF = 2 if DAMPs = 2 regardless of CD13

Excess injury triggers an overwhelming immune response.

[25, 49, 95]

18

IRF3 (3) = TRIF (3)

TRIF activates IRF3

[25, 49, 95]

19

IFN-β (3) = IRF3

Active IRF3 transcriptionally activates IFN-β

[19, 49, 73, 96, 97]

18

ROS (2) = 1 IFNβ = 2 - > to intracellular model

High levels of IFN-β induce ROS

[49, 87, 88, 90,91,92]

19

ROS = 0 otherwise

Low levels of IFN-β do not induce ROS.

[49, 87, 88, 90,91,92]

20

MyD88 = DAMPs (3)

DAMPs bind TLR4 and activate MyD88 from the cell surface.

[98,99,100]

21

pIRAK = MyD88 (3)

Activated MyD88 enables IRAK phosphorylation/activation.

[98,99,100]

22

NF-kB = 0 if M2 = 1 and (pIRAK = 0 or 1)

M2 macrophages dampen NF-kB activity and halt inflammation unless overwhelming response.

[98,99,100]

23

NF-kB = pIRAK (3) otherwise

pIRAK activates NF-kB.

[67, 93]

24

CCL2 = NF-kB (3)

NF-kB transcriptionally regulates CCL2

[98,99,100]

  1. *# of states for the node; **XOR - either or
  2. CCL2 and ROS - > to tissue scale